The overall objective of this proposal is to investigate the feasibility of the ruminant salivary gland as a system for the production of therapeutic human proteins. Protein therapeutics is currently in increased demand for the treatment of disease. Existing production systems have limitations such as low capacity, high cost and lack of appropriate post-translational protein modifications. Our novel system can potentially overcome all these limitations. Our specific aim is to direct the expression of a human plasma protein to the salivary gland of transgenic goats, and to achieve secretion of the recombinant protein in saliva. Ruminants produce copius amounts of saliva daily, which is highly buffered but low in protein content. The negligible protease content allows for secretion of intact, under graded protein. These are significant advantages over the purification of recombinant proteins from proteinaceous fluids, like milk or plasma. We propose to use nuclear transfer to generate transgenic animals and have chosen to work with goats due to their short gestation period compared to cows. We will also develop a method for the long-term collection of saliva. Preliminary work in cows suggests that the salivary ducts can be readily accessed for collection. Phase I support will be used to generate salivary gland-specific transgenes, establish fetal cell lines and transgenic animals using nuclear transfer, as well as, to optimize saliva collection, processing and assay development. These data will be used to design future Phase II studies with optimized constructs to generate more animals, followed by the collection of transgenic saliva, and purification of the functional recombinant protein.